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Dopaminergic and cholinergic lesions in progressive supranuclear palsy.

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ORIGINAL ARTICLES
.
Dopaminergic and Cholinergic Lesions
in Progressive Supranuclear Palsy
T
Merle Ruberg, PhD," France Javoy-Agid, PhD," Etienne Hirsch, MS," Bernard Scatton, PhD,?
Remy LHeureux,? Jean-Jacques Hauw, MD," Charles Duyckaerts, MD," Francoise Gray, MD,"
Ariel Morel-Maroger, MD,S Andre Rascol, MD,§ Michel Serdaru, MD," and Yves Agid, MD"
In 9 patients with progressive supranuclear palsy and in 27 controls, dopamine and homovanillic acid concentrations,
choline acetyltransferase (CAT) activity, and the number of E3H]spiperone and E3H]quinuclidinyl benzilate binding
sites were measured post mortem in the striatum (caudate nucleus, putamen, and nucleus accumbens), substantia
innominata, and frontal cortex. Dopamine and homovanillic acid concentrations were reduced in the caudate nucleus
and putamen but not in the nucleus accumbens or frontal cortex, indicating that the nigrostriatal dopaminergic system
is lesioned in patients with progressive supranuclear palsy (as in those with Parkinson's disease) but not the mesocortical and mesolimbic dopaminergic systems, which are lesioned in parkinsonian patients. CAT activity and
f3H}spiperone binding decreased in parallel fashion in all the structures. In the striatum, this suggests that the
cholinergic neurons, which are target cells of the nigrostriatal system, also degenerate in this disease. This might
explain the decrease in the number of dopamine receptors as well as the inefficacy of levodopa or anticholinergic
therapy in these patients. The decrease in CAT activity in the substantia innominata and the frontal cortex indicates
that the innominatocortical cholinergic system is lesioned in patients with progressive supranuclear palsy and may pIay
a role in the intellectual deterioration observed. This lesion is also found in demented patients with Alzheimer's and
Parkinson's diseases.
Ruberg M, Javoy-Agid F, Hirsch E, Scatton B, LHeureux R, Hauw JJ, Duyckaerts C, Gray F,
Morel-Maroger A, Rascol A, Serdaru M, Agid Y:Dopaminergic and cholinergic lesions in progressive
supranuclear palsy. Ann Neurol 18:523-529, 1985
Progressive supranuclear palsy (PSP) is a degenerative
neurological disease, the main clinical characteristics of
which are loss of voluntary control of vertical gaze,
dysarthria, diffuse body rigidity with dystonic extension of the neck, and dementia 128,291. In its earlier
stages, PSP can be misdiagnosed as Parkinson's disease
12 1). Histologically, the disease is characterized by extensive lesions in the midbrain, specifically cell loss,
gliosis, and neurofibrillary tangles 128, 291.
Although the nigrostriatal dopaminergic neurons
appear to degenerate in patients with PSP as in those
with Parkinson's disease 171, PSP patients do not respond well to classic antiparkinsonian therapy with
levodopa or dopamine agonists 1181. In a preliminary
investigation it was observed that the number of
dopamine receptors in the striatum of 4 patients with
PSP was reduced by almost 50% compared with both
controls and parkinsonian subjects 171. This may explain why PSP patients do not respond to dopamine
replacement therapy. However, the reason for the decrease in dopamine receptor number remains to be
determined. Two hypotheses can be advanced: ( 1) target cells of the nigrostriatal dopamine neurons-cholinergic interneurons in part [ll-may
degenerate; or
(2) the synthesis or regulation of dopamine receptors
in these patients may be defective.
A second feature of PSP that is also found in Parkinson's disease is intellectual deterioration 15, 28, 291.
O n the basis of clinical criteria, PSP has been suggested to be a subcortical dementia 151-a category
that also includes demented parkinsonian subjects
[4]-as
opposed to a cortical dementia, typified by
Alzheimer's disease. In both Parkinson's and Alzheimer's diseases, there is degeneration of the cholinergic
neurons of the substantia innominata that project to
the cerebral cortex 19, 24, 32, 33). This lesion has
been related to intellectual deterioration in both diseases [9, 22, 341. A histopathological study of 1 patient with PSP 13l ) suggests that the innominatocortical pathway is lesioned in this disease as well.
In order to explore the hypotheses concerning both
the decrease in dopamine receptor number and the
From "Laboratoire de Medicine Expirimentale, Laboratoire de
Neuropathologie Charles Foix, HBpital de la SalpCtriSre, 91
Boulevard de I'HBpital, 75005 Paris, France, tSynth6labo-LERS,
Boulevard P. V. Couturier, 92220 Bagnew, France, $HBpital de
Corbeil-Essones, 9 1 Corbeil Essonnes, France, and QHBpitalPurpan,
3 1 Toulouse, France.
Received Nov 26, 1984, and in revised form Feb 28, 1985. Accepted for publication Feb 28, 1985.
Address
requests
tO
Dr Yves Agid.
523
the striatum (caudate nucleus, putamen, and nucleus
accumbens), the frontal cortex, and the substantia innominata.
Table 1 Characteristics of 27 Controh
and 9 Patients with Progressive Supranuclear Palsy
~
Characteristic
Age (yr)
Sex
Premortem severity of disease‘
Postmortem delay (hrYi
Duration of disease (yr)
Treatment with psychoactive
drugs (no. treated)
Levodopa
Bromocriptine
Chlorpromazine
Clonidine, yohimbine
Levomepromazine
Cimetidine, metoclopramide
Methyldopa, chlorazepate
Control
Group
PSP
Group
Material and Methods
77.8 2 1.8“ 68.0 2 2.4b
18M, 9F
5M, 4 F
2.8 -+. 0.3
1.9 t 0.5
11.4 ? 1.1 13.0 i 0.5
..
6.1 ? 0.7
‘Mean t SEM.
bValue significantly different from control value a t p < 0.05 (Snident’s f test).
‘Premonem severity index calculated as described in text.
%me elapsed between death and freezing of b m n .
‘Five patients received treatment until the day of death. Shght initial improvement was reported in 4 patients.
PSP = progressive supranuclear palsy; M = male; F = female
in psp, we
have measured the activity of choline acetyltransferase
and the concentrations Of dopamine and its
metabolite homovanilk acid WVA) as indices of
cholinergic and dopaminergic innervation. We have
also measured f3H}spiperone and [3H}quinucIidynyl
benzilate (f3H]QNB) binding sites as indices of
dopaminergic and cholinergic transmission potential in
State of the innominatocortic~
Twenty-seven control brains from subjects with no known
neurological or psychiatric diseases and 9 brains from patients with clinically and histopathologically diagnosed PSP
were examined (Table 1). The clinical features that provided
the basis for the diagnosis of PSP are given in Table 2. The
clinical diagnosis was confirmed histologically in 8 of the 9
patients. The distribution of neurofibrillary tangles in the
brains of 7 of the PSP patients is presented in Table 3 and is
consistent with the data originally presented by Steele and
co-workers C28, 297.
Preterminal anoxia and hypovolemia were also evaluated
on scales of 0 to 3 from information reported in the case
histories of both the controls and PSP patients. The sum of
these two scores (maximum total, 6) constitutes an index of
premortem suffering [20) (Table l ) ,which permits comparison of the controls and PSP patients with respect to premortem conditions that may have affected the quality of the
samples.
In addition to the premortem suffering index, the activity
of glutamic acid decarboxylase (GAD) was also assayed [ 121
in the frontal cortex, caudate nucleus, and putamen because
this enzyme is particularly sensitive to premortem suffering
[3,8].Widespread decreases in GAD activity would indicate
that nonspecific factors might be responsible for observed
biochemical alterations. In the PSP patients studied, GAD
activity was decreased only in the putamen (Table 4). This
be a lesion specific to the disease rather than the
result of suffering caused by premortem conditions.
Brains were stored after postmortem examination at
- 70°C. Brain structures were dissected from tissue sections
without thawing and then pulverized on dry ice. Not all
Table 2. Clinical Symptom” of Patients with Progressive Supranuclear Palsy
Patient No.
Symptom
Axial hypertonia and
postural instability
Dysarthria
Ophthalmoplegia
Dystonia
Grasping reflex
Catatonia
Pyramidal syndrome
Psychomotor retardationb
Reactivity to levodopa
182
218
244
26 1
3 14
339
364
412
422
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
NI
NI
NI
NI
NI
NI
NI
NI
+
+
+
+
+
+
NI
?
?
+
+
+
+
NI
+
+
+
+
&
0
NI
NI
NI
NI
+
+
+
0
0
0
+
NI
0
+
+
+
0
f
+
+
+
+
+
0
+
“The symptoms listed in this table are those essential for the diagnosis of PSP. Information concerning patients was obtained by retrospective
analysis of the patient histories.
hsc
Psychomotor retardation” refers to a constellation of symptoms: slowness of ideation, inertia, defective motivation, and difficulty in changing
intellectual strategy.
+ = symptom noted in the last examination recorded before death; 0 = absence of symptom expressly indicated; NI
moderately effective for a short period.
524 Annals of Neurology Vol 18 No 5 November 1985
=
no information; t
=
Table 3.Neuropatbologic Findings” in 7 Patients with Progressive Supranuclear Palsy
Patient No.
364
412
0
0
0
+++
+++
0
0
0
0
0
0
0
0
++
0
Brain Region
182
218
26 I
339
Frontal cortex
Occipital cortex
Temporal cortex
Hippocampus (Ammon’s horn)
Caudate nucleus
Putamen
Pallidum
Thalamus
Subthalamic nucleus
Substantia innominata (basal nucleus)
Septum
Substantia nigra
Interpeduncular nucleus
Peduncular reticulum
Pretectal area
Superior colliculus
Inferior colliculus
Reticular formation (medulla oblongata)
Locus ceruleus
Pontine nucleus
Floor of fourth ventricle
Reticular formation (pons)
Bulbar olive
Cerebellar cortex
Dentate nucleus
Spinal cord
0
0
0
++
0
0
0
0
0
+
++
+
+
++
+++
0
+
+
++
++
++
++
++
++
++
+++
+++
+++
++
++
++
++
0
-
++
++
0
0
0
0
++
+
0
++
0
0
0
++
-
+
++
++
++
++
+++
++
++
0
++
++
++
0
++
0
+
0
++
++
0
0
+
++
++
++
0
-
+++
+
+
+
+
++
++
++
+
0
++
++
++
0
++
+++
++
+
+++
0
0
++
++
++
++
++
+
++
++
++
++
0
0
++
++
++
++
0
++
++
+++
++
++
++
+
+++
+++
++
++
++
++
++
+
++
++
++
0
++
++
++
++
++
++
0
0
-
-
++
+++
422
++
++
++
0
0
++
++
++
-
++
++
0
++
0
++
++
++
++
0
0
+
Twenty-six brain regions were examined microscopically ( X 20) for neurofibrillary tangles. Formol-fixed paraffin sections were stained either
with hematoxylin-eosin or Bodian’s protargol plus lux01 fast blue. In addition to the findings reported here, moderate to severe cell loss was
reported in the dentate nucleus of all but 1 of these patients (No. 182). Neuropathological examination of the eighth patient (No. 314),
performed in another laboratory, indicated cell loss in the substantia nigra, dentate nucleus, and pallidum. No neuropathological data could be
obtained for the ninth patient (No. 244). but the clinical data were compatible with the diagnosis of PSP: The first symptom observed was
disinterest followed by slowness of movement, postural instability and dysarthria; four years later, axial hypertonia became evident, with flexed
posture and dystonic extension on the right side; three years later, palsy of voluntary vertical eye movements was seen. Moderate cortical atrophy
was seen on computed tomographic scan, and levodopa and bromocriptine treatments were ineffective. Following progressive worsening of
symptoms, the patient died 10 years after the first symptoms became evident.
0 = not studied; - = none observed; + = slight changes; + + = moderate changes; + + + = severe changes.
Table 4. GAD Activity” i n Controls and
Patients with Progressive Supranuclear Palsy
Brain Region
~~~~
Putamen
Caudate nucleus
Frontal cortex
~~
Controls (n)
PSP Patients (n)
%
42.0 f 5.8 (26)
46.6 5 9.4 (14)
52.1 -C 4.4 (24)
21.3 f 6.3 (8)
44.7 2 12.1 ( 7 )
37.9 2 7.8 (7)
NS
NS
~
-49b
~
‘GAD activity is expressed as nanomoies of C 0 2 produced per milligram of
protein per hour ( f SEM).
‘Value significantly different from control value at p < 0.05 (Student’s t test).
G A D = ghtamic acid decarboxylase; PSP = progressive supranuclear palsy;
NS = no significant difference.
structures studied were available for each of the patients; the
number of patients in each assay group is indicated in Tables
4 , 5 , and 6. {3H)Spiperone binding in the substantia innominata was performed o n pools of tissue from controls
and PSP patients.
Dopamine and H V A concentrations [26), [3H]spiperone
binding 171, C A T activity, 3H-QNB binding, and proteins
[25] were assayed as previously described.
The investigators who performed the clinical, neuropathological, and biochemical studies were blind to each other’s
results.
Student’s t test was used for comparison of means. Linear
regression (least-squares method) was used to calculate correlation coefficients.
Ruberg et al: PSP: Dopaminergic and Cholinergic Lesions
525
Table 5 . Dopamine concentration^,^ HVA Levels, and {'H}Spiperone
Bindingb in Controls and Patients with Progressiwe Supranuclear Palsy
Brain Region
Putamen
DA
HVA
HVNDA
C3Hlspip
Caudate nucleus
DA
HVA
HVNDA
13Hlspip
Nucleus accumbens
DA
HVA
HVNDA
L3H1spip
Frontal cortex
DA
HVA
HVAIDA
PHIspip
Substantia innominata
13Hlspip
Controls (n)
PSP Patients (n)
Difference (96)
3982 ? 393 (21)
6360 -e 486 (12)
2.06 ? 0.34 ( 1 1 )
202 +. 13 (26)
434 t 118 ( 8 )
3023 ? 715 ( 8 )
12.06 i 2.94 ( 8 )
118 Ifr 15 (9)
- 89'
2722
4048
1.66
164
k
325 (22)
364 (14)
0.22 ( 1 3 )
13 ( 2 4 )
379 ? 85 ( 7 )
2335 i 592 (7)
7.17 2 1 . 0 9 ( 7 )
86 2 1 1 (9)
- 86'
- 43d
3003
6159
2.52
142
?
375 (10)
?
409 (10)
&
0.30 (10)
13(13)
2668 2 5 0 0 ( 7 )
5443 ?: 922 ( 6 )
2.61 ? 0.65 ( 7 )
80 t 12 ( 8 )
NS
NS
NS
- 44d
2.94
309
120
51
2
0.55 ( 8 )
136 ( 8 )
23 ( 8 )
4 (22)
3.63 2 0.63 ( 6 )
371 i 1 3 6 ( 7 )
104 ? 4016)
33 i 7 ( 8 )
NS
NS
NS
- 34'
2
2
2
?
2
k
2
5
15'
-51'
585'
- 42'
432'
- 48'
- 67
"Expressed as nanogram per gram of tissue (mean ? SEMI.
hDetermined with a single saturating concentration of the ligand (0.5 nM), determined previously 171, and expressed as femtomoles per
milligram of protein (mean SEM).
Significant difference (Student's t test): ' p < 0.001; ' p < 0.005; ep < 0.05.
'Only one value obtained.
*
PSP = progressive supranucleac palsy; HVA = homovanillic acid; DA = dopamine; E3H]spip = E3H]spiperone; NS
difference.
Results
As seen in Table 5, dopamine levels were reduced by
more than 85(% and HVA levels by approximately
50% in the caudate nucleus and putamen of PSP patients; however, these levels were not reduced in the
nucleus accumbens or frontal cortex. The number of
C3H}spiperone binding sites was reduced by almost
50% in the striatum (putamen 42%, caudate nucleus
48%, nucleus accumbens 44%), less in the frontal cortex (34%), and more in the substantia innominata
(67%). Like the number of E3H)spiperone binding
sites, CAT activity (Table 6) was reduced by about
50% in the striatum (putamen 50%, caudate nucleus
4096, nucleus accumbens 61%),less in the frontalcortex
(2196),and more in the substantia innominata (70%).
The number of {3H]QNB binding sites was similar
in controls and PSP patients in all the structures except
the substantia innominata, where a considerable (26%)
but nonsignificant ( p < 0.08) decrease was observed.
Significant correlations were found between the caudate nucleus and putamen of PSP patients for HVA
levels ( v = 0.91, p < 0.01), CAT activity (Y = 0.74, p
526 Annals of Neurology Vol 18 No 5
=
no significant
< 0.05), and C3H]spiperone binding ( Y = 0.75, p <
0.05). Correlations were also sought between the
biochemical data and the number of neurofibrillary
tangles (NFTs) observed in the 7 patients for whom
detailed neuropathological data were available (Table
3). A significant negative correlation was found between the number of NFTs and the number of
[?H}spiperone binding sites ( r = 0.79, p < 0.05). Inverse relationships were also observed between NETS
and dopamine concentrations in the putamen ( v =
0.59), frontal cortex (Y = 0.64), and substantia innominata ( Y = 0.45). In the substantia innominata,
NFTs were negatively related to CAT activity ( r =
0.42) and positively related to the number of muscarinic binding sites ( r = 0.71). There was no correlation
between the measured biochemical or neuropathological parameters and either age, postmortem delay, or
drug treatment.
Discussion
The decrease in dopamine and HVA concentrations
(Table 5) in the putamen and caudate nucleus of pa-
November 1985
Table 6. CAT Activity“ and
Brain Region
Putamen
CAT
C’HIQNB
Caudate nucleus
CAT
t’H1QNB
Nucleus accumbens
CAT
[’HIQNB
Frontal cortex
CAT
t3H)QNB Bindingb in Controls and Patients with Progressive Supranuclear Palsy
Controls (n)
PSP Patients (n)
111.5 ? 7.9 (26)
491 f 5.0(27)
56.0
512
-t
5.8 (24)
33 (25)
44.1
694
lr.
78.9 2 l l . O ( l 3 )
715 -t 2 6 ( 1 4 )
30.8
691
?
5.6 % 0.4 (21)
408 2 1 3 ( 2 3 )
4.4
421
38.9
247
11.8
184
PHIQNB
Substantia innominata
CAT
PHIQNB
73.7
673
%
?
-t
k
6.0 (11)
29(13)
Difference
6.5 ( 9 )
35(9)
- 50‘
NS
5.0(9)
59(8)
- 40*
NS
3.9 ( 8 )
32(7)
-61‘
NS
* 0.6 ( 8 )
2
?
f
?
15 ( 8 )
-21‘
NS
f
3.5 ( 8 )
13(9)
- 70‘
- 26 (NS)
?
(s)
“Expressed as nanomoles of acetylcholine produced per millgram of protein per hour (mean 2 SEM).
bDetermined with a single saturating concentration of the ligand (4 nM) as determined previously [ 2 5 ] and is expressed as femtomoles per
milligram of protein (mean 2 SEM).
Statistical significance was assessed with Student’s t rest: ‘p < 0.001; “p < 0.005; =p < 0.05.
PSP = progressive supranuclear palsy; CAT
difference
=
choline acetyltransferase; [3H]QNB
tients with PSP indicates that the nigrostriatal
dopaminergic system is damaged in this disease. The
neuropathological data (Table 3) confirm that there is
severe cell damage in the substantia nigra of PSP patients. Striatal HVA concentrations decrease less than
dopamine levels, however. The resulting increase in
the HVNdopamine ratio (Table 5 ) suggests that
dopamine release from the remaining dopaminergic
neurons is increased and may reflect a presynaptic
compensatory mechanism, as described in animal
models of striatal dopamine depletion 12, 27). These
results confirm preliminary data {7f. Decreased dopamine concentrations in 2 PSP patients were also reported by Jellinger and colleagues [lbf.
The lesion of the nigrostriatal system in PSP patients
is comparable in magnitude to the nigrostriatal lesion
in parkinsonian patients. In the latter, this lesionwhich results in the disinhibition of dopaminoceptive cholinergic interneurons in the striatum {l)-is
thought to be responsible for the akinesia {6f. The
akinesia can consequently be treated by the administration of either levodopa and direct dopamine receptor agonists or cholinergic antagonists, both of which
will decrease cholinergic hyperactivity in the striatum.
PSP patients show little or no response to either type
of treatment 113, 15, 16, 18). The decrease in the
number of dopamine receptors ([3H)spiperone binding sites) (see Table 5 ) observed in the striatum of the
PSP patients studied here may explain the inefficacy of
levodopa treatment, although it may be the loss of the
=
[3H]quinuclidynyl benzilate; NS
=
no significant
dopaminoceptive cholinergic neurons in the striatum
of PSP patients that is, in fact, responsible. Loss of
these cells should result in decreased cholinergic transmission in the striatum of PSP patients, unlike those
with Parkinson’s disease. Both dopamine replacement
therapy and anticholinergic treatment, intended to decrease cholinergic hyperactivity, may therefore be inappropriate rather than ineffective for the treatment of
PSP. It would perhaps be more advisable to attempt to
correct the effect of the cholinergic deficiency on
striatal output pathways.
Whereas the nigrostriatal dopaminergic system is
lesioned in both patients with PSP and those with Parkinson’s disease, the present data indicate that the
mesocortical and mesolimbic systems, which are
lesioned in patients with Parkinson’s disease [14, 23,
261, seem to be intact in patients with PSP; dopamine
concentrations in the frontal cortex and nucleus accumbens are similar to control values (Table 5). As
dementia is characteristic of both diseases, it may be
inferred that some form of intellectual deterioration
can be manifested without a lesion of the dopaminergic cells innervating the cortex or limbic system.
Although the dopaminergic innervation of the cerebral cortex and the nucleus accumbens is not damaged
in patients with PSP, the number of dopamine receptors is nevertheless reduced by approximately 409%
(Table 5), as in the other brain areas studied. The observed decreases in [’Hfspiperone binding are therefore not a direct consequence of the dopaminergic le-
Ruberg et al: PSP: Dopaminergic and Cholinergic Lesions 527
sion and may, in fact, be generalized in this disease
since all the structures examined were affected.
However, the number of C3H)spiperone binding
sites does decrease in parallel with CAT activity in all
of the structures studied (Table 6), suggesting that the
decreases measured by these two assays are related.
Because most cholinergic interneurons in the striatum
are considered to be dopaminoceptive, it seems probable that the decreases in both CAT activity and
t3H)spiperone binding sites result from a loss of these
cells, at least in the putamen and caudate nucleus. Cell
damage in the striatum is reflected by the presence of
NETs; actual cell loss is more difficult to visualize histologically, as the cholinergic cells in the striatum represent only 1% of striatal neurons (1 11.
The neuropathological lesions and the decrease in
CAT activity are more severe in the putamen than in
the caudate nucleus. In addition, G A D levels indicate
that GABAergic interneurons [ 197 are also affected in
the putamen but not in the caudate nucleus. Lesions
in the two striatal structures, seem, therefore, to be
both asymmetrical and coordinated, as CAT activity,
[3H]spiperone binding, and HVA levels in the putamen are correlated with those in the caudate nucleus.
Studies on the topographical organization of nigral and
ventrotegmental projections in experimental animals
have shown that the putamen is innervated by cells
located caudally and laterally in the substantia nigra,
whereas the caudate nucleus is innervated by more
rostral and medial nigral cells and the nucleus accumbens by the most medial cells, those in the ventrotegmental area [lo, 301. In light of this topography, it
should be determined whether lesions of the substantia nigra-ventrotegmental region in PSP patients affect
more particularly the lateral and caudal parts of the
substantia nigra, while the medial region, including the
ventrotegmental area, is spared.
The decrease in CAT activity in both the substantia
innominata and frontal cortex and the presence of
numerous NFTs in the substantia innominata (nucleus
basalis) suggest that the innominatocortical cholinergic
pathway is damaged in patients with PSP, as an earlier
histopathological study of 1 patient indicated ( 3 11.
However, CAT activity was reduced to a much greater
extent in the substantia innominata (70%) than in the
frontal cortex (21%). Loss of afferent cholinergic projections to the substantia innominata would explain
this difference. A cholinergic projection from the nucleus interstitialis ansae lenticularis (NIAL) to the substantia innominata (nucleus basalis of Meynert) has
been described in the cat 1171. It remains to be determined whether this pathway exists in the human brain
and if it is lesioned in PSP patients.
The existence of a NIAL-innominata pathway in
the human brain and a lesion of the pathway in PSP
patients would explain not only the magnitude of the
decrease in CAT activity observed in the substantia
innominata of PSP patients, but other puzzling results
as well. First, it would explain the surprisingly large
number of C3H]QNB binding sites in the substantia
innominata. Second, because the cholinergic cells in
this structure seem to be cholinoceptive as well {17), it
is probable that the 26% loss of C3H}QNB binding
sites in the substantia innominata of our PSP patients
reflects the loss of innominatocortical neurons. The
percentage of decrease in the density of C3H]QNB
binding sites corresponds, indeed, to the percentage of
decrease in CAT activity in the frontal cortex (21%).
The paradoxical observation that, in spite of an appreciable decrease in muscarinic receptor density in the
substantia innominata, C3H]QNB binding sites seem to
increase as a function of cell damage (NETs) in this
structure might then reflect the development of hypersensitivity in response to a lesion of the putative
NIAL-innominata neurons.
The nature and extent of the cholinergic lesions of
the substantia innominata and the cerebral cortex are
important elements in the debate surrounding the concepts of cortical and subcortical dementia. CAT activity, which decreases in the cerebral cortex and substantia innominata in both Parkinson’s disease and Alzheimer’s disease, is thought to reflect destruction of
the innominatocortical neurons and has been related to
the degree of intellectual deterioration in those patients (9, 22, 291. The relatively small decrease in cortical CAT activity observed in the patients studied
here may reflect the relatively mild intellectual deterioration described in the case histories of the patients,
which is considered typical of this disease r28, 291.
However, Alzheimer’s disease, Parkinson’s disease,
and PSP seem to represent three different cases if the
relative decreases in CAT activity in the cortex and
substantia innominata are compared. In Alzheimer’s
disease, the decrease is greater in the cortex (approximately 50%) (241 than in the substantia innominata (approximately 35%) 1247, suggesting that
cholinergic neurons intrinsic to the cortex may be
lesioned as well; in Parkinson’s disease, the decreases
in both structures are similar (approximately 40%) [9};
and in PSP, the decrease is greater in the substantia
innominata than in the cortex. We wonder, then,
whether multiple cholinergic lesions are involved (intrinsic to the cortex, afferent to the substantia innominata, innominatocortical), the severity and configuration of the lesions differing in the three diseases.
In conclusion, the nigrostriatal dopaminergic system
is lesioned in patients with PSP as in those with Parkinson’s disease, confirming preliminary data [ 7 ) , but the
mesocortical and mesolimbic dopaminergic systems remain intact, in contrast to what is seen in Parkinson’s
disease patients. The loss of dopamine receptors previously observed 171 has also been confirmed and was
528 Annals of Neurology Vol 18 No 5 November 1985
found in all structures studied. In the striatum, the loss
may be due to degeneration of the cholinergic target
neurons, as the decrease in receptor number parallels
the decrease in CAT activity in the other structures as
well, but the existence of a generalized dopamine receptor deficiency cannot yet be excluded. In PSP, as
well as in Parkinson’s disease and Alzheimer’s disease,
the cholinergic deficiency in the cortex and substantia
innominata most likely reflects a lesion of the innominatocortical pathway. The present results suggest
that the cholinergic afferent pathway to the substantia
innominata is lesioned as well. A more detailed analysis of the cholinergic lesions in these three dementing
diseases is essential for comprehension of cholinergic
involvement in dementing processes.
The authors thank Drs J. L. Montastruc, M. Baudrimont, and N.
Kopp for their kind collaboration, and N. Le Balc’h for her excellent
technical assistance.
References
1. Agid Y ,Guyenet P, Glowinski J, et al: Inhibitory influence of
the nigrostriatal dopamine system on the striatal cholinergic
neurons in the rat. Brain Res 8:488-429, 1975
2. Agid Y, Javoy F, Glowinski J: Hyperactivity of remaining
dopaminergic neurones after partial destruction of the nigrostriatal dopaminergic system in the rat. Nature [New Biol]
245~150-151, 1973
3. Agid Y, Ploska A, Monfort JC, Javoy-Agid F: Striatal glutamate
decarboxylase values, indicative of hospital where patient died.
Lancet 1:280, 1984
4. Albert ML: Subcortical dementia. In Katzman R, Terry RD,
Beck K (eds): Alzheimer’s Disease: Senile Dementia and Related Disorders. New York, Raven, 1978, pp 173-180
5. Albert ML, Feldman RG, Willis AL: The “subcortical dementia”
of progressive supranuclear palsy. J Neurol Neurosurg
Psychiatr 37:121-130, 1974
6. Bernheimer H , Birkmayer W, Hornykiewicz 0, et al: Brain
dopamine and the syndromes of Parkinson and Huntington. J
Neurol Sci 20:415-455, 1973
7. Bokobza B, Ruberg M, Scatton 8, et ak 3H-spiperone binding,
dopamine and HVA concentrations in Parkinson’s disease and
supranuclear palsy. Eur J Pharmacol99:167-175, 1984
8. Bowen DM, Smith CB, White P, Davison AN: Neurotransmitter-related enzymes and indices of hypoxia in senile dementia
and other abiotrophies. Brain 99:459-496, 1976
9. Dubois B, Ruberg M, Javoy-Agid F, et al: subcortico-cortical
cholinergic system is affected in Parkinson’s disease. Brain Res
288~213-218, 1983
10. Fallon JH, Moore RY: Catecholamine innervation of the basal
forebrain. IV. Topography of the dopamine projection to the
basal forebrain and neostriatum. J Comp Neurol 180:545-580,
1978
11 Fibiger HC: The organization and some projections of cholinergic neurons of the mammalian forebrain. Brain Res Rev 4:327388, 1982
12 Gaspar P, Javoy-Agid F, Ploska A, Agid Y:Regional distribution of neurotransmitter synthesizing enzymes in the basal ganglia of human brain. J Neurochem 34:278-283, 1980
13. Jackson JA, Jankovic J, Ford J: Progressive supranuclear palsy:
clinical features and response to treatment in 16 patients. Ann
Neurol 13:273-278, 1983
14. Javoy-Agid F, Agid Y: Is the mesocortical dopaminergic system
involved in Parkinson disease? Neurology (NY) 30:13261330, 1980
15. Jellinger K. Progressive supranuclear palsy. Acta Neuropathol
(Berl) 19:347-352, 1971
16. Jellinger K, Riederer P, Tomonga M: Progressive supranuclear
palsy: clinicopathological and biochemical studies. J Neural
Transm [Suppll 16:lll-128, 1980
17. Kimura H , McGeer PL, Peng F, McGeer EG: Choline acetyltransferase-containing neurons in rodent brain demonstrated by
immunohistochemistry. Science 30:1057-1059, 1980
18. Klawans HL Jr, Ringel S P Observations on the efficacy of LDOPA in progressive supranuclear palsy. Eur Neurol 5 : 115129, 1971
19. McGeer PL, McGeer EG: Evidence for glutamic acid decarboxylase-containing interneurons in the neostriatum. Brain Res
911331-335, 1975
20. Monfort JC, Javoy-Agid F, Hauw JJ, et al: Brain glutamate
decarboxylase in Parkinson’s disease: an index of premortem
severity. Brain (in press)
21. Perkin GD, Lees AJ, Stern GM, Kocen RS: Problems in the
diagnosis of progressive supranuclear palsy. J Can Sci Neurol
5~167-173, 1978
22. Perry EK, Tomlinson BE, Blessed G, et al: Correlation of cholinergic abnormalities with senile plaques and mental test scores
in senile dementia. Br Med J 2:1457-1459, 1978
23. Price KS, Farley IJ, Hornykiewicz 0: Neurochemistry of Parkinson’s disease: relation between striatal and limbic dopamine.
In Roberts PJ, Woodruff GN, Iversen LL (eds): Dopamine.
Advances in Biochemical Psychopharmacology, vol 19. New
York, Raven, 1978, pp 293-309
24. Rossor MN, Garrett NJ, Johnson AJ, et al: A postmortem
study of the cholinergic and GABA systems in senile dementia.
Brain 105:313-330, 1982
25. Ruberg M, Ploska A, Javoy-Agid F, Agid Y:Muscarinic binding
and choline acetyltransferase activity in Parkinsonian subjects
with reference to dementia. Brain Res 232:129-139, 1982
26. Scatton B, Javoy-Agid F, Rouquier L, et al: Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in
Parkinson’s disease. Brain Res 275:321-328, 1983
27. Schultz W: Depletion of dopamine in the striatum as an experimental model of Parkinsonism: direct effects and adaptive
mechanisms. Prog Neurobiol 18:121-166, 1982
28. Steele JC: Progressive supranuclear palsy. Brain 95693-704,
1972
29. Steele JC, Richardson JC, Olzsewski J: Progressive supranuclear
palsy. Arch Neurol 10:333-359, 1964
30. Szabo J: Distribution of striatal afferents from the mesencephalon in the cat. Brain Res 188:3-21, 1980
31. Tagliavini F, Pilleri G, Gemignani F, Lechi A: Neuronal loss in
the basal nucleus of Meynert in progressive supranuclear palsy.
Acta Neuropathol 61:157-160, 1983
32 Whitehouse PJ, Hedreen JC, White CL 111, Price DL: Basal
forebrain neurons in the dementia of Parkinson disease. Ann
Neurol 13:243-248, 1983
33. Whitehouse PJ, Price DL, Struble RG, et al: Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain.
Science 215:1237-1239, 1982
34. Wilcock GK, Esiri MM, Bowen DM, Smith CCT: Alzheimer’s
disease: correlation of cortical choline acetyltransferase activity
with the severity of dementia and histological abnormalities. J
Neurol Sci 57:407-417, 1982
~
Ruberg e t al: PSP: Dopaminergic and Cholinergic Lesions
529
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